Cytotoxic T lymphocytes (hereinafter referred to as “CTL”s) are considered to be an important factor counteracting cancers.
The infiltration of CTLs exhibiting cytotoxicity against tumor cells at tumor sites of a cancer patient can be observed. A tumor antigen, which is a molecule targeted by such tumor specific CTLs, is broken down in a cell into peptides (tumor epitope peptides) comprising 8 to 11 amino acids, binds to a human leukocyte antigen (hereinafter referred to as “HLA”) which is a major histocompatibility antigen, and is then presented on the surface of a tumor cell. CTLs recognize complexes comprising HLA and the tumor antigen peptide, and attack tumor cells. CTLs thus recognize tumor cells through the tumor antigen's HLA restriction.
HLAs are cell membrane antigens expressed on almost all cells, and are broadly classified into Class I antigens and Class II antigens. HLAs recognized together with epitope peptides by CTLs are classified as Class I antigens. HLA Class I antigens are further classified as HLA-A, HLA-B, HLA-C, etc., and their genes have subtypes. For example, HLA-A is polymorphous and has A1, A2, A24, A26, etc. subtypes. HLAs for each human individual are not therefore always identical, and CTLs can even recognize these HLA subtypes when recognizing a complex of an HLA Class I antigen and a tumor epitope peptide. Further, epitope peptides capable of binding to HLAs are known to have a peptide sequence motif (patterned sequence) capable of binding to one of each type of HLAs. Accordingly, for induction and/or activation of CTLs, it is essential to select peptides comprising the motif capable of binding to different types of HLAs for every patient.
Ep-CAM is a molecule widely expressed on the surface of cancer cells of epithelial origin, and acts as an intermediary for non-calcium dependent cell-to-cell adhesion. Ep-CAM is also known as EGP-2, 17-1A, GA733-2, or KSA. Ep-CAM is highly expressive in many tumors derived from various histological origins such as the large intestine, lungs, head and neck, mammary glands, etc., and its expression is regional in normal epithelial cells. Further, since tumor progression and Ep-CAM expression level correlate, the detection of Ep-CAM expression is useful as a marker for diagnosing minimally present tumor metastases and in predicting a patient's prognosis.
Ep-CAM is widely expressed in cancer cells that originate from epithelial cells, but is expressed locally in normal cells. Given this, Ep-CAM is an important target in immunotherapies and gene therapies with monoclonal antibodies.
For example, it is reported that the administration of an Ep-CAM-specific murine monoclonal antibody (designated as 17-1A) to patients whose tumors had been surgically removed was effective in the prophylaxis of distant metastasis, and that 7 consecutive years of administration was effective in improving survival rates. It has also been reported that Ep-CAM-specific monoclonal antibodies designated as 17-1A are effective in reducing mortality rate and tumor recurrence when used for treating patients with large intestine cancers.
Furthermore, some recent reports disclose the fact showing the possibility of cancer treatments using CTLs targeting HLA-restricted Ep-CAM.
For example, Patent document 1 reports that HLA-A0201-restricted Ep-CAM-specific CTLs destroy epithelial tumor cells, but do not affect normal cells. Patent document 1 discloses a peptide consisting of the YQLDPKFITSI sequence represented by SEQ ID NO: 12 as an Ep-CAM 174-184 epitope peptide recognized by HLA-A0201-restricted CTLs.
T-cell response to Ep-CAM is also observed in colon and large intestine cancer patients who do not receive immunotherapy. In addition, when large intestine cancer patients are immunized with Ep-CAM expressing recombinant canary pox virus, anti Ep-CAM-specific CTL response is derived without causing autoimmune response.
Among HLA-A types in HLA Class I antigens, HLA-A24 is expressed the most among Japanese people. Consequently, HLA-A24-restricted Ep-CAM epitope peptides are presumably desirable cancer vaccines. Reported as such epitope peptides are, for example, as follows.
Patent document 2 discloses 5 types of epitope peptides, consisting of the amino acid sequence containing 9 amino acid residues, derived from SART-2 tumor antigen proteins as an HLA-A2402-restricted CTL epitope peptide.
Patent document 3 discloses 6 types of epitope peptides, consisting of the amino acid sequence containing 8 to 11 amino acid residues, derived from ART-4 tumor antigen proteins as an HLA-A2402-restricted CTL epitope peptide.
Patent document 4 discloses 7 types of epitope peptides, consisting of the amino acid sequence containing 8 to 11 amino acid residues, derived from p56luk proteins (tumor antigen proteins coded by luk gene) abnormally expressed in large intestine cancer cells and small cell lung cancer cells as an HLA-A2402-restricted CTL epitope peptide obtained from a cell line established from an esophagus cancer patient.
Patent document 5 discloses 4 types of PI-9-derived peptides, consisting of the amino acid sequence containing 9 to 10 amino acids, obtained from KE4 tumor cell line-derived cDNA library as an HLA-A2402-restricted CTL epitope peptide obtained from a cell line established from an esophagus cancer patient.
Patent document 6 discloses 17 types of epitope peptides, consisting of the amino acid sequence containing 9 to 10 amino acids, of PI-9-derived peptides obtained from a 11 to 18 pulmonary adenocarcinoma cell line cDNA library as an HLA-A2402-restricted CTL epitope peptide obtained from a cell line established from a lung cancer patient.
Patent document 7 discloses an epitope peptide which consists of 9 to 10 amino acid residues, has a motif capable of binding to HLA-A24.1 (HLA-A2402), and has a first conserved residue of Y, F, or W toward the N-terminal, and a second conserved residue of F, I, W or M toward the C-terminal, wherein the first and second conserved residues are separated by 6 to 7 residues.
As exemplified above, various HLA-A2402-restricted CTL epitopes among tumor-related antigens have been identified; however the expression of tumor antigens varies depending on histological origins, individual cancer patient and each patient's lesion, and therefore further new epitopes are expected to be specified.
Further, since CTL derivation by Ep-CAM epitope peptide capable of binding to an HLA-A2402 molecule has not yet been confirmed, there is demand for developing new cancer cell-specific Ep-CAM epitope peptides capable of binding to an HLA-A2402 molecule, and capable of inducing CTLs.    Patent Document 1:
International Patent Publication No. WO97/15597    Patent Document 2:
Unexamined Japanese Patent Application Publication No. 1999-318455    Patent Document 3:
Unexamined Japanese Patent Application Publication No. 2000-116383    Patent Document 4:
International Patent Publication No. WO2000-06595    Patent Document 5:
Unexamined Japanese Patent Application Publication No. 2001-245675    Patent Document 6:
Unexamined Japanese Patent Application Publication No. 2003-270    Patent Document 7:
Unexamined Japanese Patent Application Publication No. 1996-500103 (claim 11, etc.)